EP3864008A1 - Métabolites de [3-(4-{2-butyl-1-[4-(4-chloro-phénoxy)-phényl]-1h-imidazol-4-yl}-phénoxy)-propyl]-diéthyl-amine - Google Patents

Métabolites de [3-(4-{2-butyl-1-[4-(4-chloro-phénoxy)-phényl]-1h-imidazol-4-yl}-phénoxy)-propyl]-diéthyl-amine

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Publication number
EP3864008A1
EP3864008A1 EP19791152.2A EP19791152A EP3864008A1 EP 3864008 A1 EP3864008 A1 EP 3864008A1 EP 19791152 A EP19791152 A EP 19791152A EP 3864008 A1 EP3864008 A1 EP 3864008A1
Authority
EP
European Patent Office
Prior art keywords
phenoxy
chloro
butyl
imidazol
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19791152.2A
Other languages
German (de)
English (en)
Inventor
William Kenneth Banner
Bapu Gaddam
Dharma Rao Polisetti
Robert Carl Andrews
Samuel Victory
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
vTv Therapeutics LLC
Original Assignee
vTv Therapeutics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by vTv Therapeutics LLC filed Critical vTv Therapeutics LLC
Publication of EP3864008A1 publication Critical patent/EP3864008A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to metabolites of [3-(4- ⁇ 2-butyl-l-[4-(4-chloro-phenoxy)- phenyl]-lH-imidazol-4-yl ⁇ -phenoxy)-propyl]-diethyl-amine (also known as azeliragon). These metabolites may act as RAGE antagonists. These metabolites may also be useful in assays to measure the presence or amount of the metabolites or of the parent compound in a sample.
  • RAGE The Receptor for Advanced Glycation Endproducts
  • Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences.
  • RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al, Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al, J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al, J. Am. Soc. Nephrol. 11: 1488- 1497 (2000)), atherosclerosis (Vlassara et. al, The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al,
  • RAGE has also been implicated in Alzheimer's disease (Yan et al, Nature 382: 685-691, (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al, Nature 405: 354-357, (2000)).
  • ligands such as advanced glycation endproducts (AGEs)
  • SlOO/calgranulin/EN-RAGE, b-amyloid, CML (N e -Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes.
  • RAGE reactive oxygen species
  • CML N e -Carboxymethyl lysine
  • amphoterin to RAGE has been shown to modify expression of a variety of genes.
  • NF-kB free radical sensitive transcription factor
  • NF-KB regulated genes such as the cytokines IL- 1b, TNF- a, and the like.
  • NF-KB regulated genes such as the cytokines IL- 1b, TNF- a, and the like.
  • NF-KB regulated genes such as the cytokines IL- 1b, TNF- a, and the like.
  • NF-KB regulated genes such as the cytokines IL- 1b, TNF- a, and the like.
  • NF-KB regulated genes such as
  • MAP kinases, ERK1 and ERK2 have been shown to be activated by binding of AGEs and other ligands to RAGE.
  • transcription of RAGE itself is regulated at least in part by NF-KB.
  • Antagonizing binding of physiological ligands to RAGE therefore, is a target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.
  • RAGE antagonists including [3-(4- ⁇ 2-butyl-l-[4-(4-chloro-phenoxy)-phenyl]- lH-imidazol-4-yl ⁇ -phenoxy)-propyl]-diethyl-amine shown below (COMPOUND I), are disclosed in US Patent No. 7,361,678.
  • the present invention provides a compound selected from the group consisting of:
  • the present invention also provides methods of making a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the present invention further provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and methods of making thereof.
  • the present invention also provides methods of using a compound of the invention or a pharmaceutically acceptable salt thereof as an antagonist of RAGE or in the treatment of various medical conditions.
  • diseases or disease states may include, but are not limited to, and chronic inflammation, amyloidosis, Alzheimer's disease, cancer, tumor invasion and metastasis, kidney failure, or inflammation associated with autoimmunity, inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, hypoxia, stroke, heart attack, hemorrhagic shock, sepsis, organ transplantation, the development of diabetic complications such as increased vascular permeability, diabetic nephropathy, diabetic retinopathy, a diabetic foot ulcer, a cardiovascular complication, diabetic neuropathy, impaired wound healing, erectile dysfunction, and osteoporosis.
  • the present invention also provides methods of using a compound of the invention or a pharmaceutically acceptable salt thereof in an in vitro or an in vivo assay.
  • the in vitro or in vivo assay may be useful for measuring (either directly or indirectly) the pharmacokinetic parameters of COMPOUND I or of a compound of the invention, such as quantitating rate of absorption, quantitating the amount in tissue or plasma samples, quantitating the rate of metabolism, or quantitating the rate of excretion of COMPOUND I or a compound of the invention.
  • the present invention provides compounds that are metabolites of COMPOUND I, and these metabolites may bind to RAGE and have activity as RAGE antagonists.
  • Compounds that modulate the activity of RAGE may be useful, for example, in the treatment of various diseases associated with RAGE signaling and/or inflammation cascade.
  • the compounds of the invention may also be useful in an in vitro or in vivo assay for measuring the pharmacokinetics of COMPOUND I or of a compound of the invention.
  • the compounds of the invention are listed in Table 1 below.
  • Metabolites Ml, M2, M3, M5, M6 and M7 may be isolated from human plasma and/or bile taken from subjects who received one or more doses of COMPOUND I.
  • the binding affinity of a compound to sRAGE can be predictive of activity and potency of the compound as a RAGE antagonist.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Compounds of the invention also include all isotopes of atoms occurring in the metabolites.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • RAGE mediated disease is used herein to refer to one or more conditions, diseases or disease states including, but not limited to, acute or chronic inflammation including skin inflammation such as psoriasis, rheumatoid arthritis, atopic dermatitis and lung
  • inflammation including, asthma and chronic obstructive pulmonary disease, diabetes, diabetes related complications, renal failure, hyperlipidemic atherosclerosis associated with diabetes, neuronal cytotoxicity, restenosis, Down's syndrome, dementia associated with head trauma, amyotrophic lateral sclerosis, multiple sclerosis, amyloidosis, an autoimmune disease including inflammation associated with autoimmunity or organ, tissue, or cell transplant, impaired wound healing, periodontal disease, neuropathy, neuronal degeneration, vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, tumor invasion and/or metastasis, osteoporosis, and the development of diabetic late complications such as increased vascular permeability, nephropathy, retinopathy, and neuropathy.
  • the phrase“a subject” refers to mammalian subjects, preferably humans, who either suffer from one or more of the aforesaid diseases or disease states or are at risk for such.
  • Compounds that antagonize the interaction of RAGE with its physiological ligands are potentially useful in treating diseases or conditions that may be responsive to inhibiting of the RAGE receptor.
  • the present invention provides a method of treatment comprising: administering to a subject a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the inhibition of the interaction of RAGE with its physiological ligands.
  • the present invention provides a method for the inhibition RAGE signaling.
  • the present invention provides a method for treating a RAGE mediated disease comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a method for treating a RAGE mediated disease comprising administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be useful in the treatment of the complications of diabetes. It has been shown that nonenzymatic glycoxidation of
  • AGEs advanced glycation endproducts
  • Accumulation of AGEs in the vasculature can occur focally, as in the joint amyloid composed of AGE-B2 -microglobulin found in patients with dialysis-related amyloidosis (Miyata, T., et al., J. Clin. Invest., 92: 1243-1252 (1993); Miyata, T., et al., J. Clin. Invest., 98: 1088-1094 (1996)), or generally, as exemplified by the vasculature and tissues of patients with diabetes (Schmidt, A-M., et al., Nature Med., 1 : 1002-1004 (1995)).
  • RAGE expression is increased in endothelium, smooth muscle cells and infiltrating mononuclear phagocytes in diabetic vasculature. Also, studies in cell culture have demonstrated that AGE-RAGE interaction caused changes in cellular properties important in vascular homeostasis.
  • the compounds of the present invention may be useful in treating amyloidosis and/or Alzheimer’s Disease.
  • RAGE appears to be a cell surface receptor that binds b-sheet fibrillar material regardless of the composition of the subunits (amyloid-b peptide, AB, amylin, serum amyloid A, prion-derived peptide) (Yan, S. -D., et al., Nature, 382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)).
  • Deposition of amyloid has been shown to result in enhanced expression of RAGE. For example, in the brains of patients with
  • AD Alzheimer’s disease
  • RAGE expression increases in neurons and glia (Yan, S. -D., et al., Nature 382:685-691 (1996)).
  • the consequences of AB interaction with RAGE appear to be quite different on neurons versus microglia. Whereas microglia become activated as a consequence of AB-RAGE interaction, as reflected by increased motility and expression of cytokines, early RAGE-mediated neuronal activation is superseded by cytotoxicity at later times.
  • RAGE mediates the transcytosis of circulating Ab across the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • the effects of RAGE can be inhibited by a RAGE modulator (e.g., anti-RAGE antibody or sRAGE) (see e.g., Mackic et al., J. Clin. Invest., 102:734-743 (1998); see also Kumar et al., Neurosci., Program, p 141 (2000)).
  • RAGE antagonists may reduce the symptoms or delay onset of development of Alzheimer’s Disease, or both.
  • RAGE antagonists may delay or slow loss of cognitive performance, or may improve cognitive performance of a subject suffering from dementia of Alzheimer’s type, or both.
  • the compounds of the present invention may be useful in treating inflammation.
  • SlOO/calgranulins have been shown to comprise a family of closely related calcium -binding polypeptides characterized by two EF-hand regions linked by a connecting peptide (Schafer, B. et al., TIBS, 21 : 134-140 (1996); Zimmer, D., et al., Brain Res. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem., 272:9496-9502 (1997); Lugering, N., et al., Eur. J. Clin. Invest., 25:659-664 (1995)).
  • RAGE is a receptor for many members of the SlOO/calgranulin family, mediating their proinflammatory effects on cells such as lymphocytes and mononuclear phagocytes. Also, studies on delayed- type hypersensitivity response, colitis in IL-10 null mice, collagen-induced arthritis, and experimental autoimmune encephalitis models suggest that RAGE-ligand interaction
  • RAGE is also implicated in inflammatory diseases of the skin such as, but not limited to, atopic dermatitis, eczema, and psoriasis.
  • Psoriasis in particular is characterized by inflamed itchy lesions.
  • Psoriasis may be accompanied by arthropathic symptoms that are similar to those in seen in rheumatoid arthritis.
  • psoriasis is a polygenic autoimmune disorder.
  • Psoriatic lesions are rich in cytokines, in particular IL-l and IL-8, both potent proinflammatory mediators.
  • IL-8 in particular is a chemotactic factor for neutrophils; neutrophils are also known to synthesize and secrete S100 proteins, one of the ligands for RAGE which is implicated in propagation of the immune and inflammatory response.
  • Psoriasin, (S100A7) a new member of the S100 gene family, is a secreted protein isolated from psoriatic skin. Semprini et al. (Hum. Genet. 2002 Oct, 111(4-5), 310-3) have shown a linkage of psoriasis genetic susceptibility to distinct overexpression of S 100 proteins in skin. Therefore, a modulator of RAGE would be expected to regulate the immune response in psoriasis.
  • amphoterin is a high mobility group I nonhistone chromosomal DNA binding protein (Rauvala, H., et al., J. Biol. Chem., 262: 16625-16635 (1987); Parkikinen, J., et al., J. Biol. Chem. 268: 19726-19738 (1993)) which has been shown to interact with RAGE. It has been shown that amphoterin promotes neurite outgrowth, as well as serving as a surface for assembly of protease complexes in the fibrinolytic system (also known to contribute to cell mobility).
  • a local tumor growth inhibitory effect of blocking RAGE has been observed in a primary tumor model (C6 glioma), the Lewis lung metastasis model (Taguchi, A., et al., Nature 405:354-360 (2000)), and spontaneously arising papillomas in mice expressing the v-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad. Sci., 87:9178-9182 (1990)).
  • Airway inflammation is important in the pathogenesis of asthma. Such inflammation may give rise to significant exacerbations and increases in asthma severity, as well as to be a major factor in a decline in asthmatic status.
  • severe exacerbations of asthma there is an intense, mechanistically heterogeneous inflammatory response involving neutrophil and eosinophil accumulation and activation.
  • Neutrophils are a significant source of S 100 proteins, key ligands for RAGE implicated in the propagation of the immune response and inflammation. Therefore, modulators of RAGE would be expected to possess therapeutic value in the treatment of asthma.
  • the propagation step in the immune response in the lung driven by S100 - RAGE interaction would be expected to lead to the activation and/or recruitment of inflammatory cells, such as neutrophils, which in chronic obstructive pulmonary diseases such as emphysema, are significant sources of damaging proteases. Therefore, a RAGE modulator would be expected possess potential in the treatment of chronic obstructive pulmonary diseases.
  • the phrase“therapeutically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an subject that is being sought.
  • factors which may influence what constitutes a therapeutically effective amount include, but are not limited to, the size and weight of the subject, the biodegradability of the therapeutic agent, the activity of the therapeutic agent, the size of the effected area, as well as its bioavailability.
  • the phrase includes amounts which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a side effect, or a decrease in the rate of advancement of a disease or disorder.
  • treatment refers to the full spectrum of treatments for a given condition or disorder from which a subject is suffering, including alleviation or amelioration of one or more of the symptoms resulting from that disorder, to the delaying of the onset or progression of the disorder.
  • the present invention provides a method for treating restenosis comprising: administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the subject is suffering from diabetes.
  • the present invention provides a method for treating acute or chronic inflammation comprising: administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating dementia associated with head trauma comprising: administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the cognitive performance of the subject is improved.
  • the cognitive performance of the subject is maintained.
  • the rate of loss of cognitive performance of the subject is slowed.
  • the present invention provides a method for treating Alzheimer’s Disease comprising: administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the present invention is believed useful in alteration the course of the underlying dementing process.
  • Alzheimer’s Disease may be diagnosed by NINCDS and DSM criteria, Mini-Mental State Examination, and Clinical Dementia Rating within particular limits.
  • One aspect of the present invention includes improving cognitive performance comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof.
  • Cognitive performance may be assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), as is known in the art, which scores cognitive function on a 0 to 70 scale, with higher scores indicating greater cognitive impairment. Thus, a reduction in score demonstrates cognitive improvement.
  • ADAS-cog Alzheimer’s Disease Assessment Scale
  • Such a subject may be a human be suffering from dementia of Alzheimer's type, mild to moderate Alzheimer's Diseases, or severe Alzheimer's Disease.
  • Alzheimer’s Disease may also be assessed in a human through examination of four areas of function: General, Cognitive, Behavioral, and Activities of Daily Living. Such an assessment may be performed using a Clinician’s Interview Based Impression of Change (CIBIC or CIBIC plus).
  • One aspect of the present invention includes improvement in subject's function comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the subject's function is one or more of general, cognitive, behavioral, and activities of daily living.
  • the present invention provides a method for improving wound healing in a diabetic subject comprising: administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, so as to improve the rate of wound healing in the subject relative to an untreated wound.
  • the present invention provides a method for treating in a subject inflammation associated with transplantation of an organ, a tissue or a plurality of cells from a first site to a second site comprising: administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, so as to reduce inflammation in the subject.
  • the first and second sites are in different subjects.
  • the first and second sites are in the same subject.
  • the transplanted organ, cells or tissue comprise a cell or tissue of a pancreas, skin, liver, kidney, heart, bone marrow, blood, bone, muscle, artery, vein, cartilage, thyroid, nervous system, or stem cells.
  • At least one compound of the invention or a pharmaceutically acceptable salt thereof is utilized, either alone or in combination with one or more known therapeutic agents including azeliragon or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention may be used in adjuvant therapeutic or combination therapeutic treatments with other known therapeutic agents.
  • Alkylating agents Cyclophosphamide, nitrosoureas, carboplatin, cisplatin, procarbazine
  • Plant alkaloids Vinblastine, Vincristine, Etoposide, Paclitaxel,
  • Analgesics Aspirin
  • NSAIDs Nonsteroidal anti-inflammatory drugs: Ibuprofen, Naproxen,
  • DMARDs Disease-Modifying Antirheumatic drugs: Methotrexate, gold
  • Antipsychotics Haloperidol, Thioridazine
  • Antidepressants Desipramine, Fluoxetine, Trazodone, Paroxetine
  • the present invention provides a method of treating a RAGE mediated disease, the method comprising administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a therapeutic agent selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NS AIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.
  • a therapeutic agent selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NS AIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants,
  • the present invention provides a pharmaceutical composition of the invention as described above, further comprising one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NS AIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.
  • one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NS AIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.
  • Such other therapeutic agents may be administered by a like route or different route that the compound of the invention or a pharmaceutically acceptable salt thereof.
  • the composition may contain the compound of the invention or a
  • the compound of the invention or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).
  • the method may further comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof and COMPOUND I or a pharmaceutically acceptable salt thereof.
  • the amounts of COMPOUND I or a pharmaceutically acceptable salt thereof administered per dose may be between 0.1 mg and 20 mg, and the amounts of a compound of the invention or a pharmaceutically acceptable salt thereof may be between 0.1 mg and 1,000 mg.
  • COMPOUND I or a pharmaceutically acceptable salt thereof administered per dose may be between 0.1 mg and 20 mg, and the amounts of a compound of the invention or a
  • pharmaceutically acceptable salt thereof may be between 0.0001% to 5%, or between 0.001% to 5% by weight relative to the amount of COMPOUND I or a pharmaceutically acceptable salt thereof or relative to the total weight of the pharmaceutical composition.
  • the invention further provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • pharmaceutical composition is used herein to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like.
  • parenteral as used herein, includes subcutaneous injections, intravenous, intramuscular, intraci sternal injection, or by infusion techniques.
  • compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques to form osmotic therapeutic tablets for controlled release.
  • Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti -oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in l,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the invention.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols, for example.
  • creams, ointments, jellies, solutions or suspensions, lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols etc., containing the compounds of the invention are contemplated.
  • These topical formulations may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 0.1% up to about 99% of the formulation. More usually they will form up to about 80% of the formulation.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a compound of the invention or a pharmaceutically acceptable salt thereof may be administered at a dosage level of from about 0.003 to 500 mg/kg of the body weight of the subject being treated.
  • a compound of the invention or a pharmaceutically acceptable salt thereof may be administered at a dosage range between about 0.003 and 200 mg/kg of body weight per day, every other day, or once a week.
  • a compound of the invention or a pharmaceutically acceptable salt thereof may be administered at a dosage range between about 0.1 mg to 100 mg per day, every other day, or once a week.
  • a formulation intended for oral administration to humans may contain 1 mg to 2 grams of a compound of the invention or a pharmaceutically acceptable salt thereof with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • administration to the skin may be prepared at 0.1% to 99% compound to topical excipient ratio.
  • a dosage form intended for inhaled administration of 0.01 to 200 mg of compound in a suitable carrier to deliver an inhaled dosage of compound may generally contain between from about 1 mg to about 500 mg of active ingredient.
  • This dosage may be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, size of effected area and the severity of the particular disease undergoing therapy.
  • the present invention provides a pharmaceutical composition comprising M3 or a pharmaceutically acceptable salt thereof and COMPOUND I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition comprising M3 or a pharmaceutically acceptable salt thereof and COMPOUND I or a
  • M3 or a pharmaceutically acceptable salt thereof wherein M3 or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount between 0.0001% and 5% by weight of the pharmaceutical composition. In another embodiment, M3 or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount between 0.01% and 0.5% by weight of the pharmaceutical composition.
  • a pharmaceutical composition comprises M3 or a pharmaceutically acceptable salt thereof and between 0.1 mg and 100 mg, or between 0.1 mg and 50 mg, or between 1 mg and 30 mg, or between 1 mg and 10 mg of COMPOUND I or a pharmaceutically acceptable salt thereof, wherein M3 or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount between 0.0001% and 5%, or between 0.001% and 0.01%, or between 0.01% and 1% by weight relative to the amount of COMPOUND I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition or relative to the total weight of the pharmaceutical composition.
  • Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo.
  • the present invention further includes isotopically-labeled or isotopically-labeled compounds of the invention.
  • An "isotopically" or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include, but are not limited to, 2 H (also written as D for deuterium), 3 ⁇ 4 (also written as T for tritium), and 14 C. The radionuclide that is incorporated in the instant radio- labeled compounds will depend on the specific application of that radio-labeled compound.
  • a labeled compound of the invention can be used in a screening assay or in a toxicology or a pharmacokinetic study of COMPOUND I to identify/evaluate the absorption, distribution, metabolism, and excretion profile of COMPOUND I and/or metabolites thereof.
  • isotopically enriched forms of various metabolites may be prepared by substituting d9-valeryl chloride (CD3CD2CD2CD2COCI) for valeryl chloride when synthesizing the metabolite, such that the butyl group of M1-M3 and M5-M7 is isotopically enriched in deuterium.
  • Metabolite 1 3-(4- ⁇ 2-Butyl-l-[4-(4-chloro-phenoxy)-phenyl]-lH-imidazol-4-yl ⁇ - phenoxy)-propionic acid
  • ETS Patent Nos. ETS 7,361,678 and 8,580,833) in t-butyl acrylate (50 mL) was added DBET (1 equivalent), and the mixture was heated at 100 °C for 3 hr.
  • the reaction mixture was concentrated, and a water (100 mL) and 1 : 1 ethyl acetate-hexanes mixture (100 mL) was added.
  • the mixture was stirred for 30 minutes and filtered.
  • the organic layer was isolated and concentrated. The residue was purified by column chromatography on silica gel using 1-100% ethyl acetate in hexanes as eluent.
  • Metabolite 2 [3-(4- ⁇ 2-Butyl-l-[4-(4-chloro-phenoxy)-benzyl]-lH-imidazol-4-yl ⁇ - phenoxy)-propyl] -ethyl-amine
  • Metabolite 5 2-[4-[2-butyl-4-[4-[3-(diethylamino)propoxy]phenyl]imidazol-l- yl]phenoxy]-5-chloro-phenol
  • N-[4-[4-chloro-2-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-N-[2-(4- hydroxyphenyl)-2-oxo-ethyl]pentanamide (1.3 g) was prepared from 4-acetoxyacetophenone, 4- [4-chloro-2-[(4-methoxyphenyl)methoxy]phenoxy]aniline and valeroyl chloride using previously described procedures (See US Patent Nos.
  • N-[4-[4-chloro-3-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-N-[2-(4- hydroxyphenyl)-2-oxo-ethyl]pentanamide (5.36 g) is prepared from 4-acetoxyacetophenone, 4- [4-chloro-3-[(4-methoxyphenyl)methoxy]phenoxy]aniline and valeroyl chloride using previously described procedures (See US Patent Nos.
  • Metabolite 7 3-(4- ⁇ 2-Butyl-l-[4-(4-chloro-phenoxy)-phenyl]-lH-imidazol-4-yl ⁇ - phenoxy)-propan- 1 -ol
  • One assay method to determine the concentrations of COMPOUND I and certain metabolites in human plasma is as follows. Concentrations of COMPOUND I and certain metabolites in human plasma may be measured using assays based on protein precipitation followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC- MS/MS) with a lower limit of quantitation of 0.2 ng/mL or 0.4 ng/mL for each analyte.
  • An internal standard compound of deuterated (d9) COMPOUND I, Ml, M2, M3, M5, M6 or M7 may be used to prepare an internal standard solution (0.5 mg/mL in methanol-DMSO, 90: 10 v/v).
  • HPLC conditions are as follows: column, XBridge (Waters) C18, 3.5 pM, 2.1 x 50 mm; column temperature, 45°C; mobile phase composition, mobile phase A: 0.1% formic acid and 0.05% trifluoroacetic acid (v/v/v) , mobile phase B: acetonitrile containing 0.1% formic acid and 0.05% trifluoroacetic acid (v/v/v); % mobile phase A to % mobile phase B varied from 65%/35% to 5%/95% over the 12 minute run time; flow rate, 1 mL/min. Plasma quality control samples are analyzed at low, mid, and high concentrations in each analytical batch. Similar methods may be used to assay bile samples.
  • the binding affinity of COMPOUND I and compounds of the invention to human sRAGE was measured using microscale thermophoresis.
  • Microscale Thermophoresis System (Monolith NT.l 15 Pico, NanoTemper, Inc) was used to determine the binding affinity of COMPOUND I and metabolites Ml, M2, M3, M5, M6 and M7 to recombinant human sRAGE.
  • sRAGE was labeled with NT-647-NHS fluorescence dye.
  • the raw thermophoresis data and average Kds were generated according to
  • the following assay method may be used to identify compounds that may be useful as inhibitors of binding of physiological RAGE ligands, such as SlOOb and b-amyloid, to RAGE.
  • SlOOb or b-amyloid 500 ng/l00pL/well
  • 100 mM sodium bicarbonate/sodium carbonate buffer pH 9.8
  • the plate is incubated at 4°C overnight.
  • the wells are aspirated and treated with 50 mM imidazole buffer saline (pH 7.2) (with 5mM CaCh/MgCh) containing 1% bovine serum albumin (BSA) (300 pL/well) for 1 h at room temperature.
  • the wells are aspirated.
  • Test compounds are dissolved in nanopure water (concentration: 10-100 pM). DMSO may be used as co-solvent. 25 pL of test compound solution in 4% DMSO is added, along with 75 pL sRAGE (6 nM FAC) to each well and samples are incubated for 1 h at 37°C. The wells are washed several times with 155 mM NaCl pH 7.2 buffer saline and are soaked for several seconds between each wash.
  • Non-radioactive detection is performed by adding 10 pL Biotinylated goat F(ab’)2 Anti- mouse IgG. (8.0 x 10-4 mg/mL, FAC), 5 pL Alk-phos-Streptavidin (3 x 10-3 mg/mL FAC), 0.42 pL per 5 mL Monoclonal antibody for sRAGE (FAC 6.0 x 10-3 mg/mL) to 5 mL 50mM imidazole buffer saline (pH 7.2) containing 0.2% bovine serum albumin and 5mM CaCh. The mixture is incubated for 30 minutes at room temperature.
  • the reaction is quenched with 10 pL of stop solution (0.5-1.0 N NaOH in 50% ethanol) and the absorbance is measured spectrophotometrically with a microplate reader at 405 nm.
  • Metabolite M2 was tested according to the assay method described above, employing SlOOb or b-amyloid as the RAGE ligand, and was found to possess IC50 shown below.
  • IC50 (pM) in the ELISA assay represents the concentration of compound at which 50% signal has been inhibited.

Abstract

La présente invention concerne des métabolites de [3-(4- {2-butyl-1-[4-(4-chloro-phénoxy))-phényl]-1H-imidazol-4-yl}-phénoxy)-propyl]-diéthyl-amine. Ces métabolites peuvent agir en tant qu'antagonistes RAGE. Ces métabolites peuvent également être utiles dans des dosages pour mesurer la présence ou la quantité d'un ou plusieurs métabolites du composé parent dans un échantillon.
EP19791152.2A 2018-10-10 2019-10-07 Métabolites de [3-(4-{2-butyl-1-[4-(4-chloro-phénoxy)-phényl]-1h-imidazol-4-yl}-phénoxy)-propyl]-diéthyl-amine Pending EP3864008A1 (fr)

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PCT/US2019/054928 WO2020076668A1 (fr) 2018-10-10 2019-10-07 Métabolites de [3-(4-{2-butyl-1-[4-(4-chloro-phénoxy)-phényl]-1h-imidazol-4-yl}-phénoxy)-propyl]-diéthyl-amine

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